本文選題：內(nèi)嗎啡肽　切入點(diǎn)：阿片受體　出處：《蘭州大學(xué)》2006年博士論文　論文類(lèi)型：學(xué)位論文

【摘要】：內(nèi)嗎啡肽-1(EM-1,Tyr-Pro-Trp-Phe-NH_2)和內(nèi)嗎啡肽-2(EM-2,Tyr-Pro-Trp-Phe-NH_2)是1997年發(fā)現(xiàn)的對(duì)μ阿片受體有著高親和性和選擇性的內(nèi)源性阿片肽,是公認(rèn)的μ阿片受體的內(nèi)源性配體。它們都具有強(qiáng)效的鎮(zhèn)痛作用,但是同時(shí)又具有酶解穩(wěn)定性差、不易透過(guò)血腦屏障和鎮(zhèn)痛效果不能持久等缺點(diǎn)。因此我們通過(guò)合理設(shè)計(jì),合成其類(lèi)似物,以期在某些方面得到改善。我們的另外一個(gè)重要的目的就是研究它們跟阿片受體相互作用的構(gòu)效關(guān)系,為基于內(nèi)嗎啡肽的鎮(zhèn)痛新藥的開(kāi)發(fā)提供理論依據(jù)。類(lèi)似物的改造方法主要是二聚化、側(cè)鏈修飾和碳末端修飾。本論文除了對(duì)阿片類(lèi)與內(nèi)阿片肽尤其是內(nèi)嗎啡肽的研究現(xiàn)狀做一個(gè)綜述外,主要實(shí)驗(yàn)工作有: 1.使用液相多肽合成方法設(shè)計(jì)合成了內(nèi)嗎啡肽母體以及碳末端修飾的類(lèi)似物共14個(gè)化合物;設(shè)計(jì)合成了側(cè)鏈修飾的內(nèi)嗎啡肽和morphiceptin的類(lèi)似物共12個(gè)化合物;設(shè)計(jì)合成了內(nèi)嗎啡肽-2和氮端片斷的二聚體共14個(gè)化合物。所有類(lèi)似物經(jīng)過(guò)高效液相色譜或制備板純化,分子量經(jīng)質(zhì)譜確證。 2.通過(guò)放射配體競(jìng)爭(zhēng)結(jié)合實(shí)驗(yàn)測(cè)定了以上化合物對(duì)大鼠腦膜上μ和6阿片受體的親和性和選擇性;通過(guò)離體器官生物檢定實(shí)驗(yàn)測(cè)定了它們?cè)陔嗍蠡啬c縱行肌(GPI)和小鼠輸精管(MVD)上的活性;選擇有代表性的化合物測(cè)定了小鼠熱板模型上的鎮(zhèn)痛活性和小鼠腦勻漿降解特性。 通過(guò)以上實(shí)驗(yàn),主要得出了以下結(jié)論: 1.內(nèi)嗎啡肽的碳末端酰胺為一較小的中性或弱堿性的基團(tuán)時(shí),能夠使其更加傾向于跟μ阿片受體結(jié)合,較大的基團(tuán)或酸性基團(tuán)則會(huì)降低μ阿片受體親和力,碳末端芳環(huán)的朝向能大大影響受體親和力和選擇性。 2.在內(nèi)嗎啡肽或morphiceptin的3位引入Hfe(2-amino-4-phenylbutanoic acid)或者4位引入Phg(phenylglycine)能夠較好的模擬Phe的作用,D-Phg則效果不好,3位和4位的芳環(huán)在受體結(jié)合中所扮演的角色是不同的;3位引入Hfe的類(lèi)似物能明顯延長(zhǎng)鎮(zhèn)痛作用時(shí)間,內(nèi)嗎啡肽的主要在體降解位點(diǎn)在2,3位之間。 3.內(nèi)嗎啡肽二肽或三肽片斷的二聚體能夠增強(qiáng)單體的受體親和力,內(nèi)嗎啡肽-2四肽二聚體隨著連接子長(zhǎng)度的延伸受體選擇性呈現(xiàn)一種有規(guī)律的波動(dòng)上升的趨勢(shì),在連接子長(zhǎng)度為2和12個(gè)原子時(shí),得到的類(lèi)似物在MVD上表現(xiàn)出了很好的活性。因此,通過(guò)
[Abstract]:Endomorphin EM-1 (Tyr-Pro-Trp-Phe-NH2) and endomorphine (-2n) Tyr-Pro-Trp-Phe-NH2) were identified in 1997 as endogenous opioid peptides with high affinity and selectivity to 渭 opioid receptors, which are recognized as endogenous ligands of 渭 opioid receptors. But at the same time, it has some disadvantages, such as poor stability of enzymatic hydrolysis, not easy to penetrate the blood-brain barrier and no lasting analgesic effect, so we synthesize its analogues through reasonable design. In order to improve in some ways. Another important purpose of our study is to study the structure-activity relationship of their interaction with opioid receptors. It provides a theoretical basis for the development of new analgesic drugs based on endomorphin. Side chain modification and carbon terminal modification. In this thesis, in addition to a review of opioid and endopiotin, especially endomorphine peptides, the main experimental work is as follows:. 1. Fourteen compounds of endomorphine peptide matrix and carbon terminal modified analogues were designed and synthesized by using liquid phase peptide synthesis method, and 12 compounds of side chain modified endomorphine peptide and morphiceptin analogues were designed and synthesized. A total of 14 compounds of endomorphin 2 and N-terminal dimer were designed and synthesized. All analogues were purified by high performance liquid chromatography or preparation plate and their molecular weight was confirmed by mass spectrometry. 2. The affinity and selectivity of the above compounds to 渭 and 6-opioid receptors in rat meninges were determined by radioligand competitive binding assay. The activity of GPI in guinea pig ileum longitudinal muscle (GPI) and MVD in mouse vas deferens was determined by bioassay in vitro, and the analgesic activity and the degradation characteristics of mouse brain homogenate in hot plate model were determined by selecting representative compounds. Through the above experiments, the main conclusions are as follows:. 1.When endomorphine peptide carbon terminal amide is a small neutral or weak basic group, it is more inclined to bind to 渭 opioid receptor, while larger group or acidic group decreases 渭 opioid receptor affinity. The orientation of the aromatic ring at the end of carbon greatly affects the affinity and selectivity of the receptor. 2. The introduction of Hfe(2-amino-4-phenylbutanoic acidat 3 sites of morphine peptide or morphiceptin or the introduction of Ph phenylglycine glycine at 4 bit can simulate the effect of Phe better than D-Phg. The roles of 3 and 4 aromatic rings in receptor binding are different from those of Hfe at 3 and 4 positions. The analogue can obviously prolong the time of analgesic action, The main degradation sites of endomorphin were between 2 and 3. 3. The dimer of endomorphine peptide dipeptide or tripeptide fragment can enhance the receptor affinity of monomer, and the dimer of endomorphine peptide -2 tetrapeptide dimer increases with the extension of ligand length. When the length of the connectors is 2 and 12 atoms, the obtained analogue exhibits good activity on MVD.
【學(xué)位授予單位】：蘭州大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2006
【分類(lèi)號(hào)】：R341

【參考文獻(xiàn)】

相關(guān)期刊論文 前1條

1 韓濟(jì)生,萬(wàn)有;“內(nèi)嗎啡肽”的發(fā)現(xiàn)是阿片肽研究的一次突破[J];生理科學(xué)進(jìn)展;1997年03期

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本文編號(hào)：1590140